2&#39;-substituted-cinchona alkaloids

ABSTRACT

2&#39;&#39;-SUBSTITUTED ALKALOIDS OF THE CINCHONA SERIES, ESPECIALLY 2&#39;&#39;-SUBSTITUTED QUININE, QUINIDINE, CINCHONIE, CINCHONIDINE AND DIHYDRO ANALOGS OF FORMULAS I AND II, AND THEIR SALTS, ARE PREPARED BY TREATING AR-N-OXIDES OF THE ALKALOIDS WITH THE CORRESPONDING ORGANOMETALLIC REAGENT AND, IF DESIRED, CONVERTING THE FREE BASES THUS FORMED INTO PHARMACEUTICALLY-ACCEPTABLE ACID-ADDITION SALTS. THE NEW COMPOUNDS ARE PHARMACOLOGICALLY ACTIVE, ESPECIALLY ANTIMALARIALLY AND ANTI-ARRHYTHMICALLY.

3,663,552 2'-SUBSTlTUTED-CINCHONA ALKALOIDS John P. Yardley, King ofPrussia, Royal E. Bright, Philadelphia, Richard W. Rees, Newtown Square,and Herchel Smith, Bryn Mawr, Pa., assignors to American Home ProductsCorporation, New York, N.Y.

No Drawing. Continuation-impart of application Ser. No. 692,277, Dec.21, 1967. This application Apr. 9, 1970, Ser. No. 27,119

Int. Cl. C07d 43/24 U.S. Cl. 260-284 12 Claims ABSTRACT OF THEDISCLOSURE 2'-substituted alkaloids of the cinchona series, especially2-substituted quinine, quinidine, cinchonine, cinchonidine and dihydroanalogs of Formulas I and II, and their salts, are prepared by treatingar-N-oxides of the alkaloids with the corresponding organometallicreagent and, if desired, converting the free bases thus formed intopharmaeeutically-acceptable acid-addition salts. The new compounds arepharmacologically active, especially antimalarially andanti-arrhythmically.

This application is a continuation-in-part of co-pending applicationSer. No. 692,277, entitled 2'-Substituted- Cinchona Alkaloids, filedDec. 21, 1967, now abandoned.

This invention relates to 2-substituted cinchona alkaloids. Moreparticularly, it is concerned with novel 2- substituted derivatives ofquinone, quinidine, dihydroquinine, dihydroquinidine, cinchonine,cinchonidine, dihydrocinchonine, dihydrocinchonidine, and the like. Thenew compounds, and their salts, possess valuable pharmacologicalproperties, especially anti-malarial activity and anti-arrhythmicactivity.

DESCRIPTION OF THE INVENTION The new compounds of this invention areselected from those of Formula I or II R: H Rs 1 L H N c N x Q. Q A OH III or pharmaceutically-acceptable acid-addition salts thereof, wherein Qis a radical of the formula I Il -m.

R ih hydrogen or methoxy;

R is (lower)alkyl, (loweralkenyl, (lower)alkynyl, [(lower)alkyl] N-(CHwherein n is from about 3 to about 10, cyclo(lower)alkyl,halo(lower)alkyl, halo (lower)alkenyl, aryl, or aryl substituted withfrom 1 to 5 halo, (lower)alkyl, (lower)alkenyl, (lower)alkynyl,halo(lower)alkyl, trifluoromethyl, (lower)alkoxy or halo(lower)alkenyl:groups, aryl(lower)alkyl, or aryl (lower)alkyl groups wherein the arylmoiety is substituted with from 1 to 5 halo, (lower)alkyl, (lower)al-United Patent Oflice 3,663,552 Patented May 16, 1972 kenyl, (lower)alkynyl, halo(lower)alkyl, trifiuoromethyl, (lower)alkoxy orhalo(lower)alkenyl groups; and

R is ethyl or vinyl, provided, however, when R is methoxy in Formula I,R is other than phenyl.

Special mention is made of particularly important compounds of thisinvention. These are compounds of Formula I wherein R is hydrogen ormethoxy, R is (lower)alkyl, trifluoromethyl, [(lower)alkyl] (CH whereinn is from about 3 to about 10, (lower)alkoxyphenyl,(trifluoromethyl)phenyl, benzyl, halobenzyl, (trifiuoromethyl)benzyl, orhalophenyl; and R is ethyl or vinyl; and compounds of Formula II whereinR is hydrogen or methoxy, R is lower(alkyl) phenyl,tlifiuoromethyhphenyl, [(lower)alkyl] N-(CH wherein n is from about 3 toabout 10, (lower)alkoxyphenyl, benzyl, halobenzyl,(trifluoromethyl)benzyl or halophenyl; and R is ethyl or vinyl.

Especially useful embodiments of this invention are:

2'-methylquinidine, a compound of Formula II, wherein R is methoxy, R ismethyl and R is vinyl, either as the free base or as the acid additionsalt with hydrogen chloride;

2'-ethylquinidine, a compound of Formula II, wherein R is methoxy, R isethyl and R is vinyl, either as the free base or as the acid additionsalt with hydrogen chloride;

'-phenylquinidine, a compound of Formula II, wherein R is methoxy, R isphenyl, and R is vinyl, either as the free base or as the acid additionsalt with hydrogen chloride; and

2'-(4-chlorophenyl)-quinidine, a compound of Formula II, wherein R ismethoxy, R is 4chlorophenyl and R is vinyl, either as the 'free base oras the acid addition salt with hydrogen chloride;

2'-cyclopropylquinidine, a compound of Formula II, wherein R is methoxy,R is cyclopropyl and R is vinyl, either as the free base or as the acidaddition salt with hydrogen chloride;

2'-n-propylquinidine, a compound to Formula II, wherein R is methoxy, Ris n-propyl and R is vinyl, either as the free base or as the acidaddition salt 'with hydrogen chloride;

2-isopentylquinidine, a compound of Formula II, wherein R is methoxy, Ris isopentyl and R is vinyl, either as the free base or as the acidaddition salt with hydrogen chloride;

2'-[(dimethylamino)-n-propyl] quinidine, a compound of Formula 11,wherein R is methoxy, R is dimethylamino-n-propyl and R is vinyl, eitheras the free base or as the acid addition salt with hydrogen chloride;

2-t-butylquinidine, a compound for Formula II, wherein R is methoxy, Ris t-butyl and R is vinyl, either as the free base or as the acidaddition salt with hydrogen chloride;

2-[p-(trifiuoromethyl)phenyl]quinidine, a compound of Formula II,wherein R is methoxy, R is p-(trifluoromethyl) phenyl and -R is vinyl,either as the free base or the acid addition salt with hydrogenchloride;

2'-(p-fiuorobenzyl)quinidine, a compound of Formula II, wherein R ismethoxy, R is p-fluorobenzyl and R is vinyl, either as the free base oras the acid addition salt with hydrogen chloride;

2'-n-propyldihydroquinidine, a compound of Formula II, wherein R ismethoxy, R is n-propyl and R is ethyl, either as the free base or as theacid addition salt with hydrogen chloride;

2'-phenyldihydroquinidine, a compound of Formula II, wherein R ismethoxy, R is phenyl and R is ethyl, either as the free base or as theacid addition salt with hydrogen chloride;

2'-(p-chlorophenyl)dihydroquinidine, a compound of Formula II, wherein Ris methoxy, R is p-chlorophenyl and R is ethyl, either as the free baseor as the acid addition salt with hydrogen chloride.

2'- [p- (trifluoromethyl phenyl] dihydroquinidine, a compound of'Formula II, wherein R is methoxy, R is p-(trifluoromethyl)phenyl and Ris ethyl, either as the free base or as the acid addition salt withhydrogen chloride;

2'-(p-fluorophenyl)quinine, a compound of Formula I, wherein R ismethoxy, R is p-fluorophenyl and R is vinyl, either as the free base oras the acid addition salt with hydrogen chloride;

2'-(p-methoxyphenyl)quinine, a compound of Formula I, wherein R ismethoxy, R is p-methoxyphenyl and R is vinyl, either as the free base oras the acid addition salt with hydrogen chloride;

2'-(p-chlorophenyl)quinine, a compound of Formula I, wherein R ismethoxy, R is p-chlorophenyl and R is vinyl, either as the free base oras the acid addition salt with hydrogen chloride;

2-[p-(trifluoromethyl)phenyl]quinine, a compound of Formula I, wherein Ris methoxy, R is p-(trifiuoromethyl)phenyl and R is vinyl, either as thefree base or as the acid addition salt with hydrogen chloride;

2-(a,a,a-trifiuoro-p-tolyl dihydroquinine, a compound of Formula I,wherein R is methoxy, R is p-(trifluoromethyl) phenyl and R is ethyl,either as the free base or as the acid addition salt with hydrogenchloride.

Those skilled in the art will recognize that the instant compounds are2'-substituted derivatives of the cinchona alkaloids. Thus, quinine,dihydroquinine, cinchonidine and dihydrocinchonidine are the parentsubstances for the instant compounds of Formula I; and quinidine,dihydroquinidine, cinchonine and dihydrocinchonine are the parentsubstances for compounds of Formula II. These alkaloids provide valuablestarting materials for the instant compounds, as will be outlined indetail hereinafter.

When used herein and in the appended claims, the term lower(alkoxy)contemplates hydrocarbonoxy radicals, straight and branched chain,containing from about 1 to about 6 carbon atoms, and includes methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, n-pentoxy, nhexoxy, 2methylpentoxy, and the like. The term (lower)alkyl contemplateshydrocarbon radicals, straight and branched chain, containing from about1 to about 6 carbon atoms, and includes methyl, ethyl, npropyl,i-propyl, n-butyl, t-butyl, n-pentyl, n-hexyl, 2- methylpentyl, and thelike. The term (lower)alkenyl" contemplates monoand di-olefinichydrocarbon radicals, straight and branched chain, containing from about2 to about 6 carbon atoms, and includes vinyl, alkyl, Z-methyl-Z-butenyl, isopropenyl, 1,3-butadienyl, 2-pentenyl, 3- hexenyl and thelike. The term (lower)alkynyl comtemplates monoand diacetylenichydrocarbon radicals, straight and branched chain, containing from about2 to about 6 carbon atoms, and includes ethynyl, propargyl, Z-butynyl,1,3-butadynyl, 2-pentynyl, 3-hexynyl and the like. The termcyclo(lower)alkyl contemplates saturated cyclic hydrocarbon radicalscontaining from about 3 to about 6 carbon atoms, and includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The termhalo when used by itself or in association with (lower) alkyl,(lower)alkenyl or aryl contemplates halogens, and includes fluorine,chlorine, bromine, and iodine. The term aryl contemplates mono-, diandtricarbocyclic aryl radicals, and includes phenanthryl, naphthyl andphenyl radicals, which can be unsubstituted or substituted with from 1to substituents as defined above, with reference to Formulae I and II.

As will be readily apparent to those skilled in the art, compounds ofFormulae I and II are bases and react with and form useful salts withorganic and inorganic acids, such as hydrochloric, hydrobromic,sulfuric, phosphoric, methanesulfonic, acetic, lactic, succinic, maleic,aconitic, phthalic, tartaric, and the like. These salts are especiallyuseful to prepare soluble pharmaceutical dosage forms.

In addition, certain of them are more rapidly absorbed than the freebases, permitting quicker onset of action and higher blood levels.

The compounds of this invention can be prepared in several differentways. One especially convenient manner comprises reacting amono-ar-N-oxide of Formula III or IV wherein R and R are as hereinabovedefined, with an organomagnesium halide of the formula wherein R is ashereinabove defined and X is chloride, bromide or iodide until formationof the grignard adduct corresponding to Formula I and II issubstantially complete, decomposing said adduct with water or an acidsuch as hydrogen chloride or an abvious chemical equivalent thereof,such as ammonium chloride, and recovering the free base compound ofFormula I or II, or, if desired, converting the free base, by reactionwith an organic or inorganic acid into an acid addition salt, andrecovering the said salt.

The mono-ar-N-oxides of Formulae III or IV can be prepared by treatingthe corresponding alkaloid with hydrogen peroxide in glacial acetic acidby the method of M. Ishikawa et al., Skika Zairo Kenkyusho Hokoku, 2,181-188 (1961) or alternately by the mehod of E. Ochiai, J. Pharm. Soc.(Japan), 68, 109 (1948). The organomagnesium halides are easily preparedby methods well known to those skilled in the art. In this connection,reference is made to the compilation in Kharash and Reinmuth, GrignardReactions of Non-Metallic Substances," Prentice-Hall, Inc., New York,1954, and to the specific references cited therein.

In proceeding according to the above method, the process is normallyconducted in benzene-ether mixture at the reflux point, conditions whichnormally insure a homogeneous reaction mixture but other solvents orcombinations with tetrahydrofuran, dioxane, toluene, and the like, canbe used. Brief, for example, 15-45 minute, reflux periods appear tooffer optimum reaction conditions.

An alternative and often useful method for preparing the compounds ofthis invention consists in treating N- oxides of Formula III or IV withthe corresponding organo lithium compounds of the formula R LiConversion of the free bases of Formula I or H to the corresponding acidaddition salt is accomplished by treating a solution of the base in asolvent, such as a lower alcohol, i.e. methanol or isopropanol, aketone, such as acetone or an ether, such as diethyl ether, with thestoichiometrically-equivalent amount of the desired acid, thenevaporating the solvent, leaving the salt as a residue. If desired, itcan be recrystallized from a solvent, such as a lower alcohol or aketone or mixtures of such solvents. The dihydroquinine anddihydrocinchonidine of Formula I and the dihydrocinchonine anddihydroquinidine of Formula II may also be prepare by hydrogenatirig thecorresponding quinine, cinchonidine, cinchonine or quinidine. Thishydrogenation is accomplished by conventional means of hydrogenatingethenoid unsaturated, for example, by dissolving unsaturated compoundsor acid addition salts of Formula I or II in a suitable solvent, i.e.methanol, which is added to palladized charcoal and reacted withhydrogen at a temperature of about C. to about 50 C., preferably at lowto moderate pressures, e.g. from about 1 to about 3 atmospheres,preferably about 1, atmosphere until absorption of the equivalent amountor a slight excess, e.g. up to about 1.1 moles of hydrogen issubstantially complete. The catalyst used is preferably a noble metalcatalyst, finely divided or supported, on a carrier, for example,platinum or palladium, or palladium on carbon or palladium on charcoal.Following hydrogenation, the product is recovered by conventional means,i.e. filtering off the catalyst and taking the filtrate to dryness,dissolving the residue in water and basifying with a base (i.e. NaOH)and extracting with an organic solvent (i.e. CHCl and crystallizing theresidue from an appropriate solvent (i.e. ethyl alcohol).

As is mentioned hereinabove, the new 2'-substituted cinchona alkaloidsof Formulae I and II, and their salts, of this invention have been foundto possess useful pharmacological properties, especially asanti-malarials and as anti-arrhythmic agents. This makes them useful inthe treatment of conditions in the living organism responsive toadministration of active anti-malarial agents, such as the symptomscaused by malaria. In addition, they are also useful to treat conditionsin the living organism responsive to administration of activeanti-arrhythmic agents, such as cardiac arrhythmia. Such agents areeffective for the treatment of auricular fibrillation by restoringnatural rhythm. Furthermore, the instant compounds are of particularvalue for such purposes because they exhibit excellent response, have arapid onset of action and relatively low toxicity.

The compounds of this invention can be administered alone or incombination with pharmaceutically acceptable carriers, the proportion ofwhich is determined by the solubility and chemical nature of thecompound, selected route of administration and standard pharmaceuticalprac tice. For example, they may be administered orally in the form oftablets or capsules containing such excipients as starch, milk sugar,certain types of clay, and the like. They may be administeredsublingually in the form of troches or lozenges in which the activeingredient is mixed with sugar and corn syrups, flavoring agents anddyes; and then dehydrated sufficiently to make the mixture suitable forpressing into a solid, compact form. They may be administered orally inthe form of solutions which may contain coloring and flavoring agents orthey may be injected parenterally, that is intramuscularly,intravenously or subcutaneously. For parenteral administration they maybe used in the form of a sterile solution containing other solutes, forexample, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound selected. Furthermore, itwill vary with the particular subject under treatment. Generally,treatment is initiated with small dosages, substantially less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under the circumstances isreached. It will generally be found that when the composition isadministered orally, larger quantities of the active agent will berequired to produce the same effect as a smaller quantity givenparenterally. In general, the compounds of this invention are mostdesirably administered at a concentration level that will generallyafford elfective results without causing any harmful or deleterious sideeffects. For cardiac arrythmias they are used preferably at a level thatis in the range of from about 0.1 mg./kg. to about 30 mg./ kg. per day,although as mentioned, variations will occur. For anti-malarial purposesthey are used preferably at a level that is in the range of from about 5mg./kg. to about 600 mg./kg. per day, although as mentioned, variationswill occur. However, a dosage level that is in the range of from about10 mg./'kg. to about 100 mg./kg. per day is most desirably employed inorder to achieve most effective results.

Anti-malarial activity was measured against P. berghi in mice and P.gallinaceum in chicks by methods similar to those described by T. S.Osdene, P. B. Russell and L. Rane, J. Med. Chem., 10, 431 (1967) asfollows:

Mice are infected with a lethal dose of Plasmodium berghi three daysprior to the administration of the compound at each of three doselevels. The compound test is mg./kg. of body weight. Routinely, thecompounds are administered subcutaneously in oil. The mean survival timeof infected control mice is 7.0:50 days. Extension of survival time ofchemically-treated mice is interpreted as evidence of antimalarialactivity.

In the chick test, 9-12 day-old white Leghorn cockerels of uniformstock, which are delivered to the laboratory when one day old and thenmaintained under standard conditions, including a non-medicated diet,until ready for test. Chicks on test are given intraveneous injection of0.2 ml. of heparinized hearts blood infected with Plasmodium gallinaceumand having a minimum of 9()% parasitized red blood cells. Theparasitized blood is drawn by cardiac puncture from donor birds infected72 hours earlier with Plasmodium gallinaceum. Donor strains aremaintained in separate groups of chicks, 14-l6 days old, that alsoreceived inoculations of heparinized infected hearts blood. In eachexperiment 100% of the untreated controls die within 7-296 hourspost-infection. In order to check factors such as changes ininfectivity, or in susceptibility of the host, or to detect technicalerrors, a group of infected animals treated with chloroquinine at doselevels producing definite increases in survival times is included as apositive control in every experiment.

Candidate compounds are dissolved or suspended in peanut oil. Treatmentin the chick consists of a single dose administered eithersubcutaneously or orally immediately after infection. Each experiment isdone with graded doses, and increases in dose levels of highly activecompounds are followed by increases in survival times. If an active drugis toxic for the host, its toxicity is a limiting factor to changes indosages. Deaths that occurred within 48 hours after infection andtreatment are considered as deaths due to the toxic effects of the testcompound. Chicks with survival periods of 30 days are recorded as cured.An increase of 100% in survival time is recognized as the minimumsignificantly effective response to the antimalarial activity of acandidate compound.

Anti-arrythmic activity was tested by a standard pharmacologicalprocedure similar to that described by G. S. Dawes, Brit. J. PharmacoL,1, (1946).

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples aregiven by way of illustration and are not to be construed as limitationsof this invention, many variations of which are possible withoutdeparting from the scope and spirit thereof.

EXAMPLE 1 2-methylquinidine and hydrochloride Quinidine ar-N-oxide (2.0g., 5.9 moles) in 40 ml. of anhydrous benzene is added dropwise to astirred solution of methyl magnesium iodide in ether (25 ml. 3 M, 7.510* moles) during minutes. The reaction mixture is refluxed undernitrogen for /2 hour, cooled to 10 C. and treated with ice-waterfollowed by an excess of 2 N HCl (some undissolved yellow solid isobtained at this stage; it is dissolved in warm water and added to thereaction mixture). The aqueous phase is separated, washed with ether andbasified strongly with ice-potassium hydroxide solution. Chloroform (250ml.) is added, the mixture is stirred vigorously for a few min; utes andfiltered through filter aid. The precipitate and filter aid arere-extracted with chloroform, filtered and washed with chloroform. Thechloroform layer is separated from the aqueous filtrate, washed withbrine and dried (K CO Evaporation of the chloroform affords 2.1 g.residue, readily crystallizing on trituration with methanol to give2-methylquinidine (1.5 g.) M.P. 150 C. (as the methanol solvate). NMR2.56 (3H singlet, 2'-methyl), 3.45 (3H singlet) methanol solvate, 3.82(3H singlet, 6-CH O) and no absorption below '8 p.p.m. as in quinidine,8.50 (1H doublet, ]=4.5 c.p.s., 2'-H) or guinidine ar-N-oxide 8.48 1Hdoublet, J=10 c.p.s.; 2'- l-I). The analytical sample (from methanol),M.P. 160 C. loses methanol of solvation. After drying for 5 hrs. at 80in vacuo, the product is analyzed.

AnaIysis.-Calcd. for C H N O (percent): C, 74.52; H, 7.74; N, 8.28.Found (percent): C, 74.24; H, 7.25; N, 8.32.

2-methylquinidine base is treated in 4 ml. of isopropanol with an excessof 6.6 N isopropanolic HCl (2 ml.). The product is precipitated byaddition to ether and the precipitate (550 mg.) is recrystallized fromacetone. The analytical sample crystallized from isopropanol-acetonemelts at 202-218 C., with decomposition.

Analysis.

for C21H2 N2O2Cl2' A1H2O (percent): C, 60.55; H, 6.91; N, 6.74; Cl,17.05. Found (percent): C, 60.41, 60.61; H, 7.08, 7.04; N, 6.64; CI,15.07.

EXAMPLE 2 2'-ethylquinidine and hydrochloride Quinidine-ar-N-oxide (10.0g.) in 200 ml. of anhydrous benzene is added slowly to 3 molar ethylmagnesium bromide in ether (125 ml.) under nitrogen. The mixture isrefluxed /2 hour, chilled to -10 C. and an ice-Water slurry is addedcautiously. When the decomposition is complete, 2 N HCl is added toacidify the mixture. The precipitate which remains is dissolved byaddition of more water. The layers are separated and the aqueous phasewashed once with ether. The combined organic phases are back-washed oncewith a small quantity of 2 N HCl which is added to the aqueous phase.This is then made strongly basic by the addition of an ice-aqueous KOHmixture and filtered through filter aid. The filter cake is Washedexhaustively with a CHCl :MeOH (1:1) mixture. The layers in the filtrateare separated and the aqueous phase extracted three times with CHCl Thecombined organic phase is washed with brine, dried over K CO andstripped to a glass under high vacuum. The title compound is obtained ascrystals from heptane (4.0 g.) M.P. 135-139 C. The analytical sample iscrystallized from heptane, M.P., 138-140 C.

NMR: 3 proton triplet at 5 1.23 (CH, of 2 ethyl group), 3 proton singletat 63.81 (methoxy group), multiplet 5 4.8-6.3 (vinyl group +OH), singletat 6 7.14, 7.30, 7.45, doublet at 6 7.90 (4 aromatic protons).

max.

. Analysis.-Calcd. for C H N O (percent): C, 74.96; H, 8.01; N, 7.95.Found (percent): C, 75.10; H, 8.31; N, 7.95.

2.-ethy1quinidine hydrochloride (amorphous solid, REE; 3.16 (broad)3.50, 3.93 (broad), 4.30 (shoulder) 6.20, 6.69, 6.88 is prepared fromthe base by the procedure in Example 1. Recrystallized from isopropylalcohol and ethyl ether gives a M.P. 171-175 C.

EXAMPLE 3 2-phenylquinidine and hydrochloride Quinidine-ar-N-oxide (10.0g.) in 200 ml. of anhydrous benzene is added slowly to 3 molar phenylmagnesium bromide in ether ml.) under nitrogen. After refluxing for /2hour the reaction mixture is chilled to l0 C. and an ice-water mixtureis added cautiously. When the decomposition is complete, the mixture isacidified with 2 N HCl and all of the soluble precipitate is dissolvedwith additional water. The layers are separated and the aqueous phaseWashed once with ether. The combined organic phase is backwashed oncewith a small portion of 2 N HCl which is added to the aqueous phase.This is then made strongly basic by adding ice-aqueous KOH mixture. Theprecipitate is removed by filtration through filter aid and the cake iswashed exhaustively with CHCl :MeOH (1:1).

CHCl :MeOH (1:1) The layers in the filtrate are separated and theaqueous phase is extracted three times with CHCl The combined organicphases are washed with brine, dried over K CO and solvent removed invacuo. Crystallization of the resultant glass from methanol-ether yieldsthe title compound, 4.4 g., M.P. 193-196 C.

max.

EXAMPLE 4 2-(4-chlorophenyl)quinidine and hydrochloride4-bromochlorobenzene (14.2 g.) in 15 ml. of ether is dropped into astirred mixture of 1.92 g. of magnesium metal in 25 ml. of ether andtrace of iodine at such a rate that the ether boils slowly. After thereaction has subsided, the stirred mixture is refluxed an additionalhour. This solution is cooled and filtered through a pad of glass wooland there is added at a moderate rate, while stirring, 2.0 g. ofquinidine-ar-N-oxide in 40 ml. of anhydrous benzene. After refiuxing forone-half hour, the reaction mixture is chilled to -10 C. and anice-water mixture is added cautiously. When decomposition is complete,excess 2 N HCl is added followed by additional water to dissolve all ofthe precipitate. The layers are separated and the aqueous phase iswashed once with ether. The water phase is then stirred with CHCl andmade basic with an ice-aqueous KOH mixture. The slimy precipitate isremoved by filtration through filter aid and the filter cake is washedthoroughly with CHCl MeOH (1:1). The layers in the filtrate areseparated and the aqueous phase is extracted three times with CHCl Thecombined organic phase is washed with saturated salt solution and driedover K CO Removal of solvent in vacuo and extraction of the resultantgum with heptane provides 9 the crystalline title compound (600 mg),M.P. 106- 114 C;

Recrystallization from ethyl ether provides the pure title compound,M.P. 118122 C.

2-(4chlorophenyl)quinidine hydrochloride is prepared by the proceduredescribed for the preparation of the hydrochloride in Example 1. Whenrecrystallized from isopropyl alcohol and diethyl ether demonstrates aM.P. 187-191" C.

EXAMPLE 5 2'-n-propylquinidine and hydrochloride Following the procedureof Example 2 using n-propyl magnesium bromide, a yield of 33% of theamorphous title compound is provided. Following the procedure of Example1, the amorphous title compound is converted to its dihydrochloride, acrystalline compound, M.P. 175 C.

Analysis.-Calcd for C H N O -H O (percent): C, 60.38; H, 7.49; N, 6.12;Cl, 15.52. Found (percent): C, 60.60; H, 7.23; N, 6.14; Cl, 15.92.

Using-the above procedure, the following compounds were provided inamorphous :form as the free base which is then converted into thecrystalline hydrogen chloride acid addition salt:

2-(p-methoxyphenyl)quinine, dihydrochloride, M.P. 215 C.

Analysis.Calcd for C27H30N203'2HC]. (percent): C, 64.41; H, 6.41; N,5.57; Cl, 14.08. Found (percent): C, 64.24; H, 6.58; N, 5.19; Cl, 13.86.

2'-(p-chlorophenyl)quinine, dihydrochloride, M.P. 215 C.

Analysis.--Calcd for C H N O Cl-2HCl (percent): C, 64.48; H, 5.76; N,5.52; Cl, 20.94. Found (percent): C, 61.62; H, 6.03; N, 5.24; Cl, 20.20.

2-[p-trifluoromethyDphenyl] quinine, dihydrochloride, M.P. 2102l8 C.

Analys'is.-Calcd. for C H F N O -2HCl (percent): C, 57.96; H, 5.58; N,5.01; Cl, 12.78; F, 10.18. Found (percent): C, 58.31; H, 5.07; N, 5.06;CI, 12.93; F, 9.55.

, EXAMPLE 6 2-isopentylquinidine and hydrochloride Following theprocedure of Example 2, using isopentyl magnesium bromide, a yield of17% of the amorphous title compound is provided. Following the procedureof Example 1, the amorphous title compound is converted to itsdihydrochloride, a crystalline compound, M.P. 170- 174 C.

Analysis.-Calcd. for C H N O -2HCl-2/3H O (percent): C, 62.62; H, 7.85;-N, 5.84; Cl, 14.79. Found (percent): C, 62.54; H, 7.53; N, 5.83; Cl,14.50.

EXAMPLE 7 2'-dimethylamino-n-propylquinidine Following the procedure ofExample 2, using the Grignard reagent, dimethylamino-n-propyl magnesiumbro mide, the title compound is provided as an amorphous solid havingthe molecular formula C H N O with a calculated m/e of 409.Experimentally, an m/e of 409 is confirmed. Experimental m/e isdetermined on an AEI MS-902 mass spectrometer at low resolution. Thespectras were examined for their molecular ion and major fragmentation;only the molecular ion is reported.

EXAMPLE 8 2'- [p-trifiuoromethyl phenyl] quinidine and hydrochlorideFollowing the procedure of Example 3, using p-(trifiuoromethyl)phenylmagnesium bromide, the amorphous title compound is provided in a 40%yield. The dihydro chloride is provided by the procedure set forth inExample l and melts at 198-200" C.

Analysis.-Calcd. for C27H27F3N2O2'2HC1'H2O (percent): C, 57.96; H, 5.59;N, 5.01; Cl, 12.67. Found (percent): C, 57.86; H, 5.62; N, 4.91; CI,12.83.

Following the above procedure, using the appropriate starting materials,is produced 2'-(p-fluorophenyl)quinine, M.P. C., which is converted to2'-(p-fluorophenyl)quinine, dihydrochloride, M.P. 215 C.

Analysis.-Calcd. for C H FN O -2HC1 (percent): C, 63.54; H, 5.95; N,5.70; Cl, 14.4; F, 3.87. Found (percent): C, 63.12; H, 5.82; N, 5.70;Cl, 13.8; F, 4.22.

EXAMPLE 9 2'- (p-fluorobenzyl) quinidine Following the procedure ofExample 3, using p-fluoro- 'benzyl magnesium bromide, the title compoundis provided in a 6% yield. Calculated for a molecular nformula of C H FNO with a calculated m/e of 432 which is confirmed by experimentalfindings.

EXAMPLE 10 The procedure of Example ,1 is repeated, substituting for themethyl magnesium iodide, stoichiometricallyequivalent amounts of thefollowing organo magnesium halides from which are provided thecorresponding 2'- substituted-quindines:

CH MgCl, 2'-methylquindine;

CH MgBr, 2'methylquinidine;

HCECMgBr, 2-ethynylquinidine;

CH3CH2MgCl, 2'-ethylquinidine;

CH CECMgBr, 2'-prop-1-ynylquinidine;

F CCH CH MgCl, 2- 3,3,3-trifiuoropropyl) quinidine;

H ChCHcH MgCl, 2'prop-2-enylquinidine;

CH CH CH MgCI, 2-propylquinidine;

( CH CHMgCl, 2-isopropylquinidine;

H C=CHCECMgBr, 2'-but-1-yn-3-enylquinidine;

C-H CH C E CM gBr, 2'-but-1-ynylquinidine;

fi C CBrCH CH MgBr, 2'- (3-bromobut-3-enyl quinidine;

H C=CHCH CH MgBn 2'-but-3-enylquinidine;

CH (CH CH MgCl, 2'-butylquinidine;

CH (CH CH MgBr, 2'-pentylquinidine;

( CH N- CH MgCl, 2-- 3- (dimethylamino propyl] quinidine;

(CH N--(CH MgCl, 2-[ 10- (dimethylamino decyl] quinidine;

[CH CH N(CH .;MgCl, 2'- [4- (dihexylamino) butylJquinidine;

C H MgBr, 2'-cyclopentylquinidine;

C H MgBr, 2'-cyclohexylquinidine;

3ClC H MgBr, 2'-(m-chlorophenyl) quinidine;

4-BrC H MgI, 2'- (p-chlorophenyl) quinidine;

2-CH OC H MgBr, 2'- (o-anisyl) quinidine;

2-CH CH C H MgBr, 2'- (o-ethylphenyl) quinidine;

4CH CH C H MgBr, 2- (p-ethylphenyl)quinidine;

2,3-(CH 'C H MgBr, 2'-(2,3-dimethylphenyl) quinidine;

2,4-(CH C H Mg'Br, 2-(2,4-dimethylphenyl) quinidine;

2,5-(CH C H MgBr, 2'-(2,5-dimethylphenyl) quinidine;

EXAMPLE 14 2'-cyclopropylquinidine and hydrochloric acid addition saltTo a solution of cyclopropyl lithium in diethyl ether (250 ml.),prepared from lithium (4.475 g., 646 mmoles) and cyclopropyl bromide(36.7 g., 331 mmoles) [Seyforth and Cohen, J. Organometal Chem., 1, 15(1963)] is added while stirring at -5 C. under nitrogen a solution ofquinidine-ar-N-oxide (10.0 g., 29.5 mmoles) in benzene (200 ml.). Whenthe addition is complete stirring under nitrogen is continued whileallowing the reaction mixture to warm to room temperature over a periodof one hour. The reaction is then stopped by chilling to 0-5 C., addingice-water and then 2 N HCl to dissolve the precipitate. The small amountof tar remaining is dissolved in a minimum amount of methanol Which isadded to the main two phase mixture. The layers are then separated, theaqueous phase is washed once with a small quantity of ether, then madebasic with cold 50% NaOH solution and then extracted thoroughly times)with chloroform. The combined chloroform extracts are washed withsaturated brine, dried over K CO and solvent removed in vacuo to yield adark tar which is chromatographed through a column of activatedmagnesium silicate. Fractions eluted with mixtures of 1% methanol inchloroform and 2% methanol in chloroform yield the title product as thecrystalline free base (from heptane), M.P. 59- 72" C.;

Xfif; 3.45, 6.15, 6.22, 6.39, 6.64, 6.88;.

Mass spectrum, M+ at 364 m/e peaks at 136 m/e (characteristic forquinuclidine fragment [Budzikiewicz, Djerassi, Williams, StructureElucidation of Natural Products by Mass Spectrometry, vol. 1, p. 220]),M'- m/e (methylene-t-proton from rearrangement of cyclopropyl group), M40 m/e (loss of cyclopropyl less a proton), M 135 m/e(quinoline+CH(OH)+cyclopropyl+proton+CH O). NMR signals at 1.04 and 0.95(multiplet) p.p.m. Confirm presence of cyclopropyl.

The free base (1.5 g.) is converted to the dihydrochloride (1.76 g.)M.P. 174.8 C.;

X25; 2.96-3.10, 3.45, 3.87 (broad), 4.25 (shoulder), 6.05, 6.14, 6.62,6.81, 6.99,.

by the procedure described in Example 1.

EXAMPLE 15 2'-t-butylquinidine and hydrochloride Following the procedureof Example 14 using lithio-tbutyl in place of the lithio-cyclopropyl, ayield of 11% of the title compound is provided. Following the procedureof Example 1, the title compound is converted to its crystallinedihydrochloride, C H N O -2HCl, M.P. 240 C., with a calculated m/e forthe free base of 380. Experimentally, a m/e for the free base of 380 isconfirmed.

EXAMPLE 16 2'-(p-chlorophenyl)dihydroquinidine and hydrochloride2-(p-chlorophenyl)quinidine, dihydrochloride of Example 4 (2.6 g., 5mol.) is dissolved in CH COH (100 ml.) and added to pre-reduced 5% Pd/C(0.89 g.) in 25 ml. of CH OH and hydrogenated at atmospheric pressurefor 45 minutes. Hydrogen uptake stops after 5 mmol. of H is taken up.The catalyst is then filtered off and the filtrate taken to dryness. Theresidue is dissolved in H 0 and basified by the addition of NaOHsolution. The aqueous phase is then extracted with CHCl and the combinedextracts are dried and concentrated in vacuo. The residue provides 1.02g. of crystalline product, M.P. 163-174 C.

AnaIysis.Calcd. for C H ClN O (percent): C, 71.46; H, 6.69; N, 6.41; Cl,8.10. Found (percent): C, 71.46; H, 6.80; N, 6.43; Cl, 7.80.

1 6 Following the procedure set forth in Example 1 for the preparationof acid addition salts with hydrogen chloride, the dihydrochloride ofthe title compound is prepared, M.P. l189.

EXAMPLE l7 2'-n-propyldihydroquinidine and hydrochloride Following aprocedure similar to that set forth in EX- ample 16, using2'-n-propylquinidine of Example 5, the title compound is produced, M.P.168l71C.

Analysis.-Calcd. for C H N O (percent): C, 74.96; H, 8.75; N, 7.60.Found (percent): C, 74.78; H, 8.66; N, 7.31.

Using a procedure similar to that described in Example 1, thedihydrochloride salt of the title compound is provided, M.P. 184186.

EXAMPLE 18 2-phenyldihydroquinidine, monohydrate and hydrochlorideFollowing a procedure as set forth in Example 16 using2'-phenylquinidine of Example 3, the title compound is produced, M.P.260270 C. 1

Analysis.Calcd. for C H N O -H O (percent): C, 74.25; H, 7.67; N, 6.66.Found (percent): C, 74.24; H, 7.46; N, 6.71.

Using a procedure as set forth in Example 1, the dihydrochloride salt ofthe title compound is provided, M.P. 184-187.

EXAMPLE 19 2- [p- (trifluoromethyl phenyl] dihydroquinidine andhydrochloride EXAMPLE 20 2'- [p- (trifiuoromethyl) phenyl1dihydroquinineand hydrochloride Following the procedure set forth in Example 16, using2-(a,a,a-trifluoro-p-tolyl)quinine of Example 5, the title compound isfound to be a crystalline solid with a m/e calculated of 470 and isconfirmed by experimental work. The dihydrochloride produced thereby afound to be amorphous.

EXAMPLE 21 Following the procedures set forth in Examples 16 to 20(dihydrogenation), 2'-substituted-quinidine oompounds of Example 10 areconverted into the following compounds:

1 7 2'- [3 ,5 -di (trifiuoromethyl) benzyl] dihydroquinidine; 2'-(m-fluorophenylethyl) dihydroquinidine 2'- (o-anisylethyl)dihydroquinidine; 2 (2, 3 -dimethylphenylbutyl) dihydroquinidine; 2-2,4-dimethoxyphenylethyl) dihydroquinidine; 2- 4- chlorol-naphthylethyl)dihydro quinidine; 2'- [p- (trifluoromethyl phenylethyl] quinidine.

Following the procedure of Example 1, the above compounds are convertedto their respective acid addition salts with hydrogen chloride.

EXAMPLE 22 Following the procedures set forth in Example 16 to 20(dihydrogenation), 2-substituted-cinchonine, quinine and cinchom'dinecompounds of Example 11 are converted into the following dihydrocompounds:

Following the procedure set forth in Example 1, the above compounds areconverted to their respective acid addition salts with hydrogenchloride.

What is claimed is:

1. A compound of [Formula I or II 110. n N 19. N

Q/ o, a Q/A on H (II) or a pharmaceutically-acceptable acid-additionsalt there of, wherein Q is a 4-quinolyl radical of the formula 18wherein R is hydrogen or methoxy and R is phenyl substituted in thepara-position with a halo, (1ower)alkyl, (lower)alkenyl, (lower)alkynyl, monohalo(lower)alkyl, trifluoromethyl, (lower)alkoxy, ormonohalo(lower)alkeny1 group, wherein said (lower)alkyl, (lower)alkenyl, (l0wer)alkynyl, monohalo(lower) alkyl, (lower)alkoxy, andmonohalo(lower) alkyl groups have hydrocarbon moieties of from one tosix carbon atoms; and R is ethyl or vinyl. 2. A compound as defined inclaim 1, of Formula I, wherein R is hydrogen or methoxy; R isp-(lower)alkoxyphenyl, phenyl, or p-halophenyl, and R is ethyl or vinyl.3. A compound as defined in claim 1, of Formula H, wherein R is hydrogenor methoxy; R is p-(lower)alkoxyphenyl,

phenyl, or p-halophenyl, and R is ethyl or vinyl. 4. A compound asdefined in claim 3, which is 2'-(4- chlorophenyDquinidine.

5. A compound as defined in claim 3, which is2-ptrifiuoromethyl-phenylquinidine.

6. A compound as defined in claim 3, which is2'-(pchlorophenyl)dihydroquinidine.

7. A compound as defined in claim 3, which is 2-[p-(trifluoromethyl)pheny1]dihydroquinidine.

8. A compound as defined in claim 2, which is 2-(pfluorophenyl) quinine.

9. A compound as defined in claim 2, which is 2-(pmcthoxyphenyl)quinine.

10. A compound as defined in claim 2, which is 2'(pchlorophenyDquinine.

11. A compound as defined in claim 2, which is 2-[p- (trifluoromethyl)phenyl] quinine.

12. A compound as defined in claim 2, which is 2'-[p-(trifluoromethyl)phenyl]dihydroquinine.

p- (trifluoromethyl) p-(trifiuoromethyl) References Cited UNITED STATESPATENTS 9/1925 Thomas 260284 6/1959 Rudner 260 -284 X OTHER REFERENCESDONALD G. DAUS, Primary Examiner US. Cl. X.R. 424-259

